Structure-activity studies on endothelin (16-21), the C-terminal hexapeptide of the endothelins, in the guinea-pig bronchus.
1. We describe the results of a structure-activity study in which the C-terminal hexapeptide of the endothelins, endothelin (16-21), is compared with shorter fragments; hexapeptides bearing amino-acid substitutions and the corresponding C-terminal fragments of sarafotoxins. The guinea-pig bronchus was used in this study since it is the most sensitive preparation for endothelin (16-21) thus far developed. 2. The biological results obtained with endothelin (16-21) and analogues demonstrate that the contractile activity of the C-terminal hexapeptide of endothelin on the guinea-pig bronchus depends on quite close structural requirements, strongly suggestive of a receptor interaction. The following features appear to be essential for the biological activity: (a) the C-terminal free carboxylic function; (b) the L-configuration of Trp-21; (c) the beta-carboxylic function of Asp-18; (d) the presence of Leu-17 and (e) the imidazole moiety of His-16. 3. The hexapeptide corresponding to the C-terminal portion of sarafotoxin, sarafotoxin (16-21), was devoid of biological activity. This behaviour might be related to the proposed existence of more than one receptor for the endothelin/sarafotoxin family in the guinea-pig bronchus.
Rovero
P
P
Chemistry Department, A. Menarini Pharmaceuticals, Firenze, Italy.
Patacchini
R
R
Maggi
C A
CA
D000595:Amino Acid Sequence; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D016232:Endothelins; D010446:Peptide Fragments; D010455:Peptides; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C061533:endothelin (16-21)